Certain cell lines of the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), which responds poorly to standard therapy, have recently been discovered by the candidate and former colleagues to rely on the B-cell receptor (BCR) for activation of the canonical NF:B pathway and other pathways essential for their survival. The principal goal of the application is to collaborate with the Molecular Libraries Probe Production Centers Network (MLPCN), using a cell-based primary assay already established by the MLPCN, to find small-molecule inhibitors of this process termed "chronic active BCR signaling" (CABS). The assay will be performed in a CABS-dependent line, and in combination with counterscreens and secondary assays, will be used to identify inhibitors of CABS that can be optimized to serve as chemical probes of its poorly- understood mechanisms, and candidates for drug development as targeted therapy against ABC-DLBCL. The proposed project would be a continuation of the applicant's previous investigations into how the NF:B pathway is constitutively activated in ABC-DLBCL, identifying potential therapeutic targets of increasing specificity. Finding chemical probes of CABS would advance the applicant's immediate career goals of making further discoveries about this pathway, and becoming established as an independent investigator. Finding serious candidates for drug development would advance the applicant's long-term goals of extending his research findings into the clinical arena, in keeping with his having recently joined a department which excels in the development and clinical testing of new therapies. PUBLIC HEALTH RELEVANCE: Many different types of cancer depend on specific and abnormally-activated biological pathways, and inhibitors of these pathways have the potential to provide highly effective targeted therapies with reduced side effects. When a critical pathway is found in a cancer cell line, the line can be engineered to conveniently "report" on that pathway's activity level, and thus be used to screen large libraries of chemical compounds for inhibitors of the pathway. This project will use this approach to find inhibitors of a critical pathway activated in one type of cancer of B cells (lymphomas) that responds poorly to standard therapy, helping in studies of this pathway and possibly providing candidates for development as targeted therapy.